Matrix metalloproteinases, which are referred to as MMPs, are a naturally occurring family of calcium- and zinc-dependent endopeptidases that are found in most mammals. Over-expression and activation of MMPs or an imbalance between MMPs and inhibitors of MMPs have been suggested as factors in the pathogenesis of diseases characterized by the breakdown of extracellular matrix or connective tissues.
The major component of periodontium (gingival, cementum, periodontal ligament and alveolar bone) is organic matrix. Matrix metalloproteinases (MMPs) are involved in remodelling the periodontal matrix. Destructive MMPs degrade various components of the extracellular matrix both in physiological and pathological conditions. The pathologic overproduction of destructive MMPs leads to an inappropriate and excessive degradation of matrix. The overproduction of destructive MMPs facilitates bone resorption by first degrading osteoid (the nonmineralized and newly synthesized bone matrix) and then degrading the matrix, resulting in the clinical manifestations of periodontitis including gingival recession, pocket formation, loss of attachment, tooth mobility and tooth loss.
MMP-13 is one of the major destructive MMPs that plays a role in degradation of the extracellular matrix. The level of MMP-13 expression correlates to periodontitis clinical indexes. MMP-13 is detected in diseased periodontal tissue and in gingival crevicular fluid; however, MMP-13 is not detected in healthy oral mucosa. Uitto et al. American Journal of Pathophysiology, 152(6), 1489 (1998).
Matrix metalloproteinase-13 was known as an enzyme responsible for bone resorption and cartilage destruction in rheumatoid arthritis and osteoarthritis. Elevated levels of MMP-13 are also known to exist in gingival crevicular fluid of patients with chronic periodontitis. In addition, MMP-13 is known to contribute to both bone and connective tissue destruction in patients with periodontal diseases. Ilgenli, T. et al. Oral Diseases, 12, 573 (2006).
Currently, antimicrobials, nonsteroidal anti-inflammatory agents (NSAIDs), bisphosphonates and tetracyclines used in the treatment of periodontal disease. These agents often do not provide adequate symptomatic relief and are not believed to alter the natural progression of the disease. Furthermore, powerful side effects are found with most all of these therapies. Hence, there is a great need for safe and effective therapy for these disorders.
Although there are many treatments for various aspects of periodontal disease, there remains a need to develop an improved oral composition comprising active ingredients which target destructive MMPs that facilitate bone resorption and cause tissue breakdown. In particular, there is a need to develop improved oral compositions which target MMP-13, which contributes to both bone resorption and connective tissue destruction.